Qb. Tang et al., Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes, ONCOGENE, 20(37), 2001, pp. 5164-5172
It has been shown that UVB irradiation induces expression of COX-2 and up-r
egulation of COX-2 plays a functional role in UVB tumor promotion. In this
study, we examined the cis-elements in the human COX-2 promoter that may be
responsible for the UVB induction of COX-2. Analyses with the COX-2 promot
er region revealed that the cyclic AMP responsive element near the TATA box
was essential for both basal and UVB induced COX-2 expression. This was fu
rther supported by studies using a dominant negative mutant of CREB, which
strongly inhibited the activity of COX-2 promoter. Electrophoretic mobility
shift assays indicated that CREB and ATF-I were the major proteins binding
to the COX-2 CRE. CREB and ATF-I were phosphorylated upon UVB treatment, a
nd SB202190, a p38 MAPK inhibitor, decreased the phosphorylation of CREB/AT
F-1 and suppressed COX-2 promoter activity. In contrast, treatment with for
skolin, an activator of adenylyl cyclase, led to phosphorylation of CREB an
d ATF-I and activation of COX-2 promoter. Finally, enhanced binding of phos
pho-CREB/ATF-1 to the COX-2 CRE was observed after UVB induction. Thus, one
signaling pathway for UVB induction of human COX-2 involves activation of
p38, subsequent phosphorylation of CREB/ATF-1, and activation of the COX-2
CRE through enhanced binding of phosphorylated CREB/ATF-1.